The present invention relates to the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of cloprostenol and fluprostenol analogues for the treatment of glaucoma and ocular hypertension.
Cloprostenol and fluprostenol, both known compounds, are synthetic analogues of PGF2xcex1, a naturally-occurring F-series prostaglandin (PG). Structures for PGF2xcex1(I), cloprostenol (II), and fluprostenol (III), are shown below: 
The chemical name for cloprostenol is 16-(3-chlorophenoxy)-17,18,19,20-tetranor PGF2xcex1. Monograph No. 2397 (page 375) of The Merck Index, 11th Edition (1989) is incorporated herein by reference to the extent that it describes the preparation and known pharmacological profiles of cloprostenol. Fluprostenol has the chemical name 16-(3-trifluoromethylphenoxy)-17,18,19,20-tetranor PGF2xcex1. Monograph No. 4121 (pages 656-657) of The Merck Index, 11th Edition (1989) is incorporated herein by reference to the extent that it describes the preparation and known pharmacological profiles of fluprostenol. Cloprostenol and fluprostenol are 16-aryloxy PGs and, in addition to the substituted aromatic ring, differ from the natural product PGF2xcex1 in that an oxygen atom is embedded within the lower (omega) chain. This oxygen interruption forms an ether functionality.
Naturally-occurring prostaglandins are known to lower intraocular pressure (IOP) after topical ocular instillation, but generally cause inflammation, as well as surface irritation characterized by conjunctival hyperemia and edema. Many synthetic prostaglandins have been observed to lower intraocular pressure, but such compounds also produce the aforementioned side effects which severely restrict clinical utility.
It has now been unexpectedly found that certain novel cloprostenol and fluprostenol analogues are useful in treating glaucoma and ocular hypertension. In particular, topical application of ophthalmic compositions comprising these novel cloprostenol and fluprostenol analogues result in significant IOP reduction.
The compounds useful in the present invention have the following general formula: 
wherein:
R1=H; C1-C12 straight-chain or branched alkyl; C1-C12 straight-chain or branched acyl; C3-C8 cycloalkyl; or a cationic salt moiety;
R2, R3=H, or C1-C5 straight-chain or branched alkyl; or R2 and R3 taken together may represent O;
X=O, S, or CH2;
---- represents any combination of a single bond, or a cis or trans double bond for the alpha (upper) chain; and a single bond or trans double bond for the omega (lower) chain;
R9=H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
R11=H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl;
Y=O; or H and OR15 in either configuration wherein R15 =H, C1-C10 straight-chain or branched alkyl, or C1-C10 straight-chain or branched acyl; and
Z=Cl or CF3;
with the proviso that when R2 and R3 taken together represent O, then R1xe2x89xa0C1-C12 straight-chain or branched acyl; and when R2 =R3 =H, then R1 xe2x89xa0a cationic salt moiety.

The term xe2x80x9cacylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9cacylaminoxe2x80x9d represents a group that is linked by an amino atom that is connected to a carbon atom has a double bond to an oxygen group and a single bond to a carbon atom or hydrogen atom.
The term xe2x80x9cacyloxyxe2x80x9d represents a group that is linked by an oxygen atom that is connected to a carbon that has a double bond to an oxygen atom and single bond to another carbon atom.
The term xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkeny groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group attached through an oxygen linkage.
The term xe2x80x9calkylxe2x80x9d includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be substituted with other groups, such as halogen, hydroxyl or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
The term xe2x80x9calkylaminoxe2x80x9d represents an alkyl group attached through a nitrogen linkage.
The term xe2x80x9calkynylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon triple bond. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkynyl groups include, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl and 2-pentynyl.
The term xe2x80x9carylxe2x80x9d refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, or halogen.
The term xe2x80x9ccarbonylxe2x80x9d represents a group that has a carbon atom that has a double bond to an oxygen atom.
The term xe2x80x9ccarbonylalkoxyxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to an alkoxy group.
The term xe2x80x9ccationic salt moietyxe2x80x9d includes alkali and alkaline earth metal salts as well as ammonium salts.
The term xe2x80x9ccarbonyloxylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to a second oxygen atom.
The term xe2x80x9ccycloalkylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cylopentyl and cyclohexyl.
The term xe2x80x9cdialkylaminoxe2x80x9d represents two alkyl groups attached through a nitrogen linkage.
The term xe2x80x9chalogenxe2x80x9d and xe2x80x9chaloxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The term xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
Preferred compounds include: cloprostenol isopropyl ester (Table 1, compound 1A), fluprostenol isopropyl ester (compound 1B), 16-phenoxy-17,18,19,20-tetranor PGF2xcex1 isopropyl ester (compound 2), 17-phenyl-18,19,20-trinor PGF2xcex1 isopropyl ester (compound 3), 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2xcex1) isopropyl ester (compound 4), the 3-oxa form of cloprostenol isopropyl ester (Table 2, compound 5), 13,14-dihydrofluprostenol isopropyl ester (compound 6), cloprostenol-1-ol (compound 7), and 13,14-dihydrocloprostenol-1-ol pivaloate (compound 8).
The compounds of formula (IV) are useful in lowering intraocular pressure and thus are useful in the treatment of glaucoma. Such compounds are also useful in improving optic nerve head blood flow and the treatment of optic nerve disorders (including without limitation retarding visual field loss and improving visual acuity), the latter being generally described in U.S. Pat. No. 5,773,471, the contents of which are by this reference incorporated herein. It is further contemplated that the compounds of the present inventions can be used with other medicaments known to be useful in the treatment of glaucoma or ocular hypertension, either separately or in combination. For example, the prostaglandin analogs of the present invention can be combined with (i) beta-blockers, such as timolol, betaxolol, levobunolol and the like (see U.S. Pat. No. 4,952,581); (ii) carbonic anhydrase inhibitors, such as brinzolamide; (iii) adrenergic agonists including clonidine derivatives, such as apraclonidine or brimonidine (see U.S. Pat. No. 5,811,443); and (iv) cholinergic agonists, such as pilocarpine. The disclosures of U.S. Pat. Nos. 4,952,581 and 5,811,443 are incorporated herein by this reference. The preferred route of administration is topical. The dosage range for topical administration is generally between about 0.01 and about 1000 micrograms per eye (xcexcg/eye), preferably between about 0.1 and about 100 xcexcg/eye, and most preferably between about 1 and 10 xcexcg/eye. The compounds of the present invention can be administered as solutions, suspensions, or emulsions (dispersions) in a suitable ophthalmic vehicle.
In forming compositions for topical administration, the compounds of the present invention are generally formulated as between about 0.00003 to about 3 percent by weight (wt %) solutions in water at a pH between 4.5 to 8.0. The compounds are preferably formulated as between about 0.0003 to about 0.3 wt % and, most preferably, between about 0.003 and about 0.03 wt %. While the precise regimen is left to the discretion of the clinician, it is recommended that the resulting solution be topically applied by placing one drop in each eye one or two times a day.
Other ingredients which may be desirable to use in the ophthalmic preparations of the present invention include preservatives, co-solvents and viscosity building agents.
Antimicrobial Preservatives:
Ophthalmic products are typically packaged in multidose form, which generally require the addition of preservatives to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, ONAMER M(copyright), or other agents known to those skilled in the art. Such preservatives are typically employed at a concentration between about 0.001% and about 1.0% by weight.
Co-Solvents:
Prostaglandins, and particularly ester derivatives, typically have limited solubility in water and therefore may require a surfactant or other appropriate co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; Tyloxapol(copyright); Cremophor(copyright) EL; sodium dodecyl sulfate; glycerol; PEG 400; propylene glycol; cyclodextrins; or other agents known to those skilled in the art. Such co-solvents are typically employed at a concentration between about 0.01% and about 2% by weight.
Viscosity Agents:
Viscosity greater than that of simple aqueous solutions may be desirable to increase ocular absorption of the active compound, to decrease variability in dispensing the formulations, to decrease physical separation of components of a suspension or emulsion of formulation and/or otherwise to improve the ophthalmic formulation. Such viscosity building agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose or other agents known to those skilled in the art. Such agents are typically employed at a concentration between about 0.01% and about 2% by weight.
The following Examples 1-4 describe the synthesis of compounds 5-8 (Table 2). These syntheses are representative in nature and are not intended to be limiting. Other compounds of formula (IV) may be prepared using analogous techniques known to those skilled in the art.
In the examples below, the following standard abbreviations are used: g=grams (mg=milligrams); mol=moles (mmol=millimoles); mol %=mole percent; mL=milliliters; mm Hg=millimeters of mercury; mp=melting point; bp=boiling point; h=hours; and min=minutes. In addition, xe2x80x9cNMRxe2x80x9d refers to nuclear magnetic resonance spectroscopy and xe2x80x9cCI MSxe2x80x9d refers to chemical ionization mass spectrometry.